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Phylogenetic Conservation of Glycoprotein 96 Ability to Interact with CD91 and Facilitate Antigen Cross-Presentation¹

Jacques Robert^2,*, Thaminda Ramanayake^*, Gregory D. Maniero, Heidi Morales^* and Asiya S. Chida^*

^* Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and Department of Biology, Stonehill College, Easton, MA 02357

Although the ability of gp96 to activate APCs and generate CD8 CTLs against peptides they chaperone through interaction with the endocytic receptors CD91 is supported by solid evidence, its biological relevance in immune surveillance is debated. We have used an evolutionary approach to determine whether gp96 interacts with receptors expressed on APCs and promotes MHC class I cross-presentation of minor histocompatibility Ags (H-Ags) to CTLs in the frog Xenopus. We show that in Xenopus gp96 binds the CD91 homolog at the surface of peritoneal leukocytes, and that this binding is inhibited by molar excess of unlabeled gp96 or the CD91 ligand ₂-macroglobulin, by anti-CD91 Ab and by the specific CD91 antagonist receptor-associated protein. Surface binding followed by internalization of gp96 was confirmed by fluorescent microscopy. Furthermore, adoptive transfer of peritoneal leukocytes pulsed with as little as 800 ng of gp96 chaperoning minor H-Ags, but not minor H-Ag-free gp96, induces potent CD8 T cell infiltration and Ag-specific accelerated rejection of minor H-locus disparate skin grafts. Inhibition of gp96-CD91 interaction by pretreatment with anti-CD91 Ab and receptor-associated protein impairs both CD8 T cell infiltration and acute skin graft rejection. These data provide evidence of the conserved ability of gp96 to facilitate cross-presentation of chaperoned Ags by interacting with CD91. The persistence of this biological process for >350 million years that separate mammals and amphibians from a common ancestor strongly supports the proposition that gp96 and CD91 are critically involved in immune surveillance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by T32-AI 07285 (to H.M.), R01-CA-108982-02, and R24-AI-059830 from the National Institutes of Health and MCB-0445509 from the National Science Foundation.

² Address correspondence and reprint requests to Dr. Jacques Robert, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642. E-mail address: Jacques_robert{at}urmc.rochester.edu

³ Abbreviations used in this paper: ₂-M, ₂-macroglobulin; SR-A, scavenger receptor type A; RAP, receptor-associated protein; hsp, heat shock protein; PL, peritoneal leukocyte; APBS, amphibian PBS; H-Ag, histocompatibility Ag.

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